Marina Cuchel is an Instructor in the Department of Medicine that in the course of the years has acquired clinical and laboratory skills in the field of lipid and lipoprotein metabolism. The goal of this application is to provide the candidate with the necessary in-depth knowledge of protocol development, study design and biostatistical analysis needed to become a successful independent investigator. To achieve this objective Dr. Cuchel will attend advanced academic courses, prepare a thesis leading to a Master of Science in Experimental Medicine and Translational Research and conduct a patient oriented research under the guidance of her mentor and Advisory Committee. Dr. Cuchel will be mentored by Dr. Daniel Rader, an expert in the field of lipid and lipoprotein metabolism and renowned for his contribution in patient-oriented research. The general hypothesis that the research proposal is designed to test is that subjects with high HDL-C plasma levels and coronary heart disease (CHD) have a delayed HDL catabolism due to impaired reverse cholesterol transport. The following specific aims will be addressed: Specific Aim 1: to characterize the clinical and biochemical profile of subjects with high HDL-C and CHD and compare it with that of 3 groups of matched control subjects (one of subjects with similarly high HDL-C levels and no CHD, the others of normolipidemic subjects with and without CHD). Specific aim 2: To test the hypothesis that subjects with high HDL and CHD have delayed catabolism of both the protein (apoA-I and apoA-II) and cholesterol moieties of HDL. Dr. Cuchel will conduct in vivo mechanistic studies using endogenous and exogenous labeling techniques to test this hypothesis. No systematic characterization of this unusual phenotype has been reported. Dr. Cuchel will take advantage of the extensive database of subjects with elevated HDL-C levels developed by Dr. Rader for recruitment purposes. She believes that this research proposal is relevant and timely as new strategies for raising HDL cholesterol levels are being actively developed. She is confident that, thank you to this award, she will get the appropriate training and guidance to accomplish her goal and become a successful independent investigator in patient oriented research in the field of lipid and lipoprotein metabolism.